The human natural killer-1 (HNK-1) glycan mimetic ursolic acid promotes functional recovery after spinal cord injury in mouse

Sahu, Sudhanshu Sekhar; Li, Rong; Kadeyala, Praveen Kumar; Liu, Shisong; Schachner, Melitta

doi:10.1016/j.jnutbio.2018.01.016

Cited by 25 publications

(28 citation statements)

References 60 publications

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“…Although one can expect 10 to 100 times higher concentrations to show such effects in vivo, these concentrations could be acceptable pharmacologically and economically. Importantly, within the range of these doses, ursolic acid and 5-nonyloxytryptamine have improved functional recovery in injured mice [ 37 , 38 , 39 ], with the ursolic acid used by Sahu et al [ 36 ] to show its pro-active functions in spinal cord regeneration, being derived from the screen described in the present study. Importantly also, several HNK1 mimetics have been FDA approved for other types of indications.…”

Section: Discussionmentioning

confidence: 91%

“…In the nervous system, ursolic acid is protective by reducing radiation impairment of neurogenesis, learning, and memory [ 45 ]. Furthermore, we found that ursolic acid improves functional recovery after spinal cord injury in mice [ 38 ]. Interestingly, ursolic acid is also a mimetic for the terminal trisaccharide LewisX, which plays an essential role in the development and repair of the nervous system, and represents an important post-translational modification of neural cell adhesion molecules such as L1CAM and contributes to enhancing neurite outgrowth and cell viability of cerebellar granule cells [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

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Functions of Small Organic Compounds that Mimic the HNK-1 Glycan

Wang

Theis

Kabat

et al. 2020

IJMS

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Because of the importance of the HNK-1 carbohydrate for preferential motor reinnervation after injury of the femoral nerve in mammals, we screened NIH Clinical Collection 1 and 2 Libraries and a Natural Product library comprising small organic compounds for identification of pharmacologically useful reagents. The reason for this attempt was to obviate the difficult chemical synthesis of the HNK-1 carbohydrate and its isolation from natural sources, with the hope to render such compounds clinically useful. We identified six compounds that enhanced neurite outgrowth from cultured spinal motor neurons at nM concentrations and increased their neurite diameter, but not their neurite branch points. Axons of dorsal root ganglion neurons did not respond to these compounds, a feature that is in agreement with their biological role after injury. We refer to the positive functions of some of these compounds in animal models of injury and delineate the intracellular signaling responses elicited by application of compounds to cultured murine central nervous system neurons. Altogether, these results point to the potential of the HNK-1 carbohydrate mimetics in clinically-oriented settings.

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Functions of Small Organic Compounds that Mimic the HNK-1 Glycan

Wang

Theis

Kabat

et al. 2020

IJMS

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“…Ursolic acid (3β-hydroxy-urs-12-en-28-oic-acid) is a naturally occurring pentacyclic triterpenoid identified as having HNK-1 mimetic functionality. The HNK-1-like activity of UA was confirmed using a competition assay with HNK-1 antibody binding through ELISA [140]. UA was first identified in the epicuticular waxes of apples and is also found in diverse classes of plants such as Rosmarinus officinalis (rosemary), Ocimum basilicum (basil), and some fruits such as pears and prunes.…”

Section: Human Natural Killer-1 (Hnk-1) Mimicking Natural Compoundmentioning

confidence: 91%

“…Here, we summarize a group of natural products (including semisynthetic compounds) that functionally mimic glycans, have proven neuroprotective functions, and may therefore form a novel class of therapeutics for NDs. These "natural glycomimetics" are classified based on the glycans they mimic including human natural killer-1 (HNK-1) [140], LewisX (LeX) [141], neural cell adhesion molecule L1 (L1CAM) [142], and polysialic acid (PSA) [143]. The glycan-mimicking properties of these compounds have been confirmed by competitive enzyme-linked immunosorbent assay (ELISA) using glycan antibodies.…”

Section: Glycan Mimetics From Natural Productsmentioning

confidence: 99%

Glycan Mimetics from Natural Products: New Therapeutic Opportunities for Neurodegenerative Disease

et al. 2019

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Neurodegenerative diseases (NDs) affect millions of people worldwide. Characterized by the functional loss and death of neurons, NDs lead to symptoms (dementia and seizures) that affect the daily lives of patients. In spite of extensive research into NDs, the number of approved drugs for their treatment remains limited. There is therefore an urgent need to develop new approaches for the prevention and treatment of NDs. Glycans (carbohydrate chains) are ubiquitous, abundant, and structural complex natural biopolymers. Glycans often covalently attach to proteins and lipids to regulate cellular recognition, adhesion, and signaling. The importance of glycans in both the developing and mature nervous system is well characterized. Moreover, glycan dysregulation has been observed in NDs such as Alzheimer’s disease (AD), Huntington’s disease (HD), Parkinson’s disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS). Therefore, glycans are promising but underexploited therapeutic targets. In this review, we summarize the current understanding of glycans in NDs. We also discuss a number of natural products that functionally mimic glycans to protect neurons, which therefore represent promising new therapeutic approaches for patients with NDs.

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“…UA has been shown to mimic the human natural killer (HNK)-1 and promote the regaining of motor functions and axonal regrowth in mice with a spinal cord injury via activation of MAPK and PI3K/Akt/mTOR pathways. It also reduced astrogliosis and levels of proinflammatory markers (IL-6 and TNF-α) in the acute phase of inflammation in injured spinal cords [123]. Additionally, UA administration has been indicated to reverse high-fat diet-induced cognitive impairment via inhibition of endoplasmic reticulum stress and NF-κB signaling and activating the PI3K/Akt/mTOR pathway in the mouse hippocampus [124].…”

Section: Ursolic Acidmentioning

confidence: 99%

Pistacia Genus as a Potential Source of Neuroprotective Natural Products

et al. 2019

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Neuroprotective agents are able to defend the central nervous system against acute or chronic neuronal injuries. Even with the progress made over the last decades, most of the medications prescribed for the management of neurodegenerative diseases can only reduce their symptoms and slow down their progression. Based on natural product research, there are potential effective medicinal plants and phytochemicals for modulating neuronal functions and protecting against neurodegeneration. Plants in the genus Pistacia are also among valuable natural resources for neuroprotection research based on experiences in traditional medicine. Studies have supported the value of bioactive compounds of the genus Pistacia for central nervous system disorders such as Alzheimerʼs, Parkinsonʼs, multiple sclerosis, cerebral ischemia, depression, and anxiety. Related literature has also revealed that most of the evidence on neuroprotection in the genus Pistacia is in the form of preliminary studies, mainly including models of behavior, motor function, and memory impairments in animals, neural toxicity, cerebral ischemia and seizure models, evaluation of their effects on antioxidant and inflammatory biomarkers, amyloid β aggregation, and acetylcholinesterase as well as investigations into some cellular pathways. Along with the phytonutrients in kernels such as pistachios, various phytochemicals, mostly terpenes, and phenolic compounds have also been identified in different plant parts, in particular their oleoresins, of species in the genus Pistacia. In this review, the pharmacology of neurological effects and related molecular mechanisms of the plants belonging to the genus Pistacia and its active constituents, as well as pharmacokinetics aspects, are discussed.

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The human natural killer-1 (HNK-1) glycan mimetic ursolic acid promotes functional recovery after spinal cord injury in mouse

Cited by 25 publications

References 60 publications

Functions of Small Organic Compounds that Mimic the HNK-1 Glycan

Functions of Small Organic Compounds that Mimic the HNK-1 Glycan

Glycan Mimetics from Natural Products: New Therapeutic Opportunities for Neurodegenerative Disease

Pistacia Genus as a Potential Source of Neuroprotective Natural Products

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